title: New linezolid-like 1,2,4-oxadiazoles active against Gram-positive multiresistant pathogens.
abstract: The synthesis and the in vitro antibacterial activity of novel linezolid-like oxadiazoles are reported. Replacement of the linezolid morpholine C-ring with 1,2,4-oxadiazole results in an antibacterial activity against Staphylococcus aureus both methicillin-susceptible and methicillin-resistant comparable or even superior to that of linezolid. While acetamidomethyl or thioacetoamidomethyl moieties in the C(5) side-chain are required, fluorination of the phenyl B ring exhibits a slight effect on an antibacterial activity but its presence seems to reduce the compounds cytotoxicity. Molecular modeling performed using two different approaches - FLAP and Amber software - shows that in the binding pose of the newly synthesized compounds as compared with the crystallographic pose of linezolid, the 1,2,4-oxadiazole moiety seems to perfectly mimic the function of the morpholinic ring, since the H-bond interaction with U2585 is retained.
authors.affiliation: Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Viale Andrea Doria 6, I-95125 Catania, Italy. cg.fortuna@unict.it
authors.forename: Cosimo G
authors.initials: CG
authors.lastname: Fortuna
authors.forename: Carmela
authors.initials: C
authors.lastname: Bonaccorso
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bulbarelli
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Caltabiano
authors.forename: Laura
authors.initials: L
authors.lastname: Rizzi
authors.forename: Laura
authors.initials: L
authors.lastname: Goracci
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Musumarra
authors.forename: Andrea
authors.initials: A
authors.lastname: Pace
authors.forename: Antonio
authors.initials: A
authors.lastname: Palumbo Piccionello
authors.forename: Annalisa
authors.initials: A
authors.lastname: Guarcello
authors.forename: Paola
authors.initials: P
authors.lastname: Pierro
authors.forename: Clementina E A
authors.initials: CE
authors.lastname: Cocuzza
authors.forename: Rosario
authors.initials: R
authors.lastname: Musumeci
mesh_terms: D000081:Acetamides / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D000069349:Linezolid; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D023303:Oxazolidinones / Q000737:chemistry*; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D010069:Oxadiazoles; D023303:Oxazolidinones; D000069349:Linezolid
keywords: Antimicrobial activity; Cell viability; Drug design; Linezolid; Oxazolidinones; Staphylococcus aureus